INFLUENCE OF METABOLIC AND GENETIC-FACTORS ON TUMOR-NECROSIS-FACTOR-ALPHA AND LYMPHOTOXIN-ALPHA PRODUCTION IN INSULIN-DEPENDENT DIABETES-MELLITUS

The potential role of tumour necrosis factors (TNFs) in autoimmunity a nd insulin-dependent diabetes mellitus (IDDM) led us to determine in v itro TNF-alpha and lymphotoxin-alpha (LT-alpha, TNF-beta) production i n IDDM patients according to TNF polymorphism. LT-a production of peri pheral blood mononuclear cells (PBMC) was lower in diabetic subjects ( m = 0.30 +/- 0.2 ng.10(-6) cells) than controls (m = 0.68 +/- 0.3 ng.1 0(-6) cells, p < 0.05), and early age-at-onset was correlated with low LT-a production (r(s)=0.8, p=0.0006). TNF-alpha production was the sa me in patients and controls, but patients with HbA1c greater than or e qual to 8 % had a higher TNF-a production (m = 3.05 +/- 1.2 ng.10(-6) cells) than those with HbA1c <8 % (m = 1.31 +/- 0.33 ng.10(-6) cells, p<0.05). A study of the microsatellite TNFa region close to the LTA ge ne showed that the presence of the TNFa1 allele in HLA-(DR3) subjects was associated with increased risk of IDDM. TNFa1-positive subjects (b oth patients and controls) also had lower LT-a production than other s ubjects. These results indicate that low LT-a production is an additio nal risk factor for IDDM and that poor glycaemic control in patients i s associated with enhanced PBMC TNF-alpha production which causes an i mbalance between TNF-alpha and LT-alpha production in IDDM patients.